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Effects of chronic administration of the phosphodiesterase inhibitor vardenafil on serum levels of adrenal and testicular steroids in men with type 2 diabetes mellitus

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Abstract

To investigate whether long-term, chronic treatment with the phosphodiesterase-5 inhibitor vardenafil affects adrenal and testicular steroidogenesis in diabetic men, using liquid chromatography-tandem mass spectrometry. A longitudinal, prospective, investigator-started, randomized, placebo-controlled, double-blind, clinical-trial was carried out, enrolling 54 male patients affected by type 2 diabetes mellitus diagnosed within the last 5 years. In total, 26 and 28 patients were followed for 1 year and assigned to the study and placebo group, respectively. Progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, corticosterone, 11-deoxycortisol and cortisol, were evaluated using liquid chromatography-tandem mass spectrometry. No differences were seen in sex testicular steroids between study and control group. As for the adrenal gland, steroids were considered according to the zona in which they are produced. No significant differences were seen in steroid produced in zona fasciculata. For the zona reticularis, dehydroepiandrosterone significantly decreased during treatment only in the study group (p = 0.007), with higher levels at visit 2 and 8 than other visits. The dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio significantly increased during treatment only in the verum group. Considering the adrenal zona glomerulosa, corticosterone significantly changed among visits both in both groups (p < 0.001), with higher levels at visit 2 (p = 0.028), 8 (p = 0.003), and 10 (p = 0.044), i.e., in coincidence with the complete clinical and instrumental examination performed only at these visits according to the study protocol. Chronically administered vardenafil reduces dehydroepiandrosterone levels and increases dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio as possible consequences of modulation of steroidogenic enzymes by tissue changes in cyclic adenosine monophosphate and cyclic guanosine monophosphate availability. A possibly stress-related increase in corticosterone is suggested for the first time.

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References

  1. W.L. Miller, Molecular biology of steroid hormone synthesis. Endocr. Rev. 9(3), 295–318 (1988). doi:10.1210/edrv-9-3-295

    Article  CAS  PubMed  Google Scholar 

  2. W.L. Miller, R.J. Auchus, The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32(1), 81–151 (2011). doi:10.1210/er.2010-0013

    Article  PubMed  Google Scholar 

  3. P.F. Hall, Cytochromes P-450 and the regulation of steroid synthesis. Steroids 48(3–4), 131–196 (1986)

    Article  CAS  PubMed  Google Scholar 

  4. E. Szarek, C.A. Stratakis, Phosphodiesterases and adrenal cushing in mice and humans. Horm. Metab. Res. 46(12), 863–868 (2014). doi:10.1055/s-0034-1389916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. H.S. Bose, T. Sugawara, J.F. Strauss 3rd, W.L. Miller, The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N. Engl. J. Med. 335(25), 1870–1878 (1996). doi:10.1056/nejm199612193352503

    Article  CAS  PubMed  Google Scholar 

  6. J.D. Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int. J. Impot. Res. 16(Suppl 1), S4–7 (2004). doi:10.1038/sj.ijir.3901205

    Article  CAS  PubMed  Google Scholar 

  7. R.C. Rosen, J.B. Kostis, Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am. J. Cardiol. 92(9A), 9M–18M (2003).

  8. A.T. Bender, J.A. Beavo, Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol. Rev. 58(3), 488–520 (2006). doi:10.1124/pr.58.3.5

    Article  CAS  PubMed  Google Scholar 

  9. A. Das, D. Durrant, F.N. Salloum, L. Xi, R.C. Kukreja, PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol. Ther. 147, 12–21 (2015). doi:10.1016/j.pharmthera.2014.10.003

    Article  CAS  PubMed  Google Scholar 

  10. D.A. Kass, Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. Curr. Heart Fail. Rep. 9(3), 192–199 (2012). doi:10.1007/s11897-012-0101-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. E. Takimoto, Cyclic GMP-dependent signaling in cardiac myocytes. Circulation 76(8), 1819–1825 (2012)

    Article  CAS  Google Scholar 

  12. R. Pofi, D. Gianfrilli, R. Badagliacca, C. Di Dato, M.A. Venneri, E. Giannetta, Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): How do they work? J. Endocrinol. Invest. (2015). doi:10.1007/s40618-015-0339-y

  13. M.T. Kearney, E.R. Duncan, M. Kahn, S.B. Wheatcroft, Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Exp. Physiol. 93(1), 158–163 (2008). doi:10.1113/expphysiol.2007.039172

    Article  CAS  PubMed  Google Scholar 

  14. V. Altabas, Diabetes, endothelial dysfunction, and vascular repair: what should a diabetologist keep his eye on? Int. J. Endocrinol. 2015, 848272 (2015). doi:10.1155/2015/848272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. D. Santi, A.R. Granata, A. Guidi, E. Pignatti, T. Trenti, L. Roli, R. Bozic, S. Zaza, C. Pacchioni, S. Romano, J.R. Nofer, J.R. Nofer, V. Rochira, C. Carani, M. Simoni, Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. Eur. J. Endocrinol. (2016). doi:10.1530/eje-15-1100

  16. K.G. Alberti, P.Z. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Med. 15(7), 539–553 (1998). doi:10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S

    Article  CAS  PubMed  Google Scholar 

  17. F. Fanelli, I. Belluomo, V.D. Di Lallo, G. Cuomo, R. De Iasio, M. Baccini, E. Casadio, B. Casetta, V. Vicennati, A. Gambineri, G. Grossi, R. Pasquali, U. Pagotto, Serum steroid profiling by isotopic dilution-liquid chromatography-mass spectrometry: comparison with current immunoassays and reference intervals in healthy adults. Steroids 76(3), 244–253 (2011). doi:10.1016/j.steroids.2010.11.005

    Article  CAS  PubMed  Google Scholar 

  18. R.J. Auchus, W.E. Rainey, Adrenarche—physiology, biochemistry and human disease. Clin. Endocrinol. 60(3), 288–296 (2004)

    Article  CAS  Google Scholar 

  19. A. Morelli, S. Filippi, R. Mancina, M. Luconi, L. Vignozzi, M. Marini, C. Orlando, G.B. Vannelli, A. Aversa, A. Natali, G. Forti, M. Giorgi, E.A. Jannini, F. Ledda, M. Maggi, Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145(5), 2253–2263 (2004). doi:10.1210/en.2003-1699

    Article  CAS  PubMed  Google Scholar 

  20. L. Di Luigi, P. Sgro, C. Baldari, M.C. Gallotta, G.P. Emerenziani, C. Crescioli, S. Bianchini, F. Romanelli, A. Lenzi, L. Guidetti, The phosphodiesterases type 5 inhibitor tadalafil reduces the activation of the hypothalamus-pituitary-adrenal axis in men during cycle ergometric exercise. Am. J. Physiol. Endocrinol. Metab. 302(8), E972–978 (2012). doi:10.1152/ajpendo.00573.2011

    Article  CAS  PubMed  Google Scholar 

  21. L. Di Luigi, C. Baldari, P. Sgro, G.P. Emerenziani, M.C. Gallotta, S. Bianchini, F. Romanelli, F. Pigozzi, A. Lenzi, L. Guidetti, The type 5 phosphodiesterase inhibitor tadalafil influences salivary cortisol, testosterone, and dehydroepiandrosterone sulphate responses to maximal exercise in healthy men. J. Clin. Endocrinol. Metab. 93(9), 3510–3514 (2008). doi:10.1210/jc.2008-0847

    Article  CAS  PubMed  Google Scholar 

  22. R.J. Auchus, T.C. Lee, W.L. Miller, Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J. Biol. Chem. 273(6), 3158–3165 (1998)

    Article  CAS  PubMed  Google Scholar 

  23. M. Katagiri, N. Kagawa, M.R. Waterman, The role of cytochrome b5 in the biosynthesis of androgens by human P450c17. Arch. Biochem. Biophys. 317(2), 343–347 (1995). doi:10.1006/abbi.1995.1173

    Article  CAS  PubMed  Google Scholar 

  24. F. Kuma, R.A. Prough, B.S. Masters, Studies on methemoglobin reductase. Immunochemical similarity of soluble methemoglobin reductase and cytochrome b5 of human erythrocytes with NADH-cytochrome b5 reductase and cytochrome b5 of rat liver microsomes. Arch. Biochem. Biophys. 172(2), 600–607 (1976)

    Article  CAS  PubMed  Google Scholar 

  25. S. Mapes, C.J. Corbin, A. Tarantal, A. Conley, The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17) and NADPH-cytochrome P450 reductase (reductase) but not 3beta-hydroxysteroid dehydrogenase/delta5-4 isomerase (3beta-HSD). J. Clin. Endocrinol. Metab. 84(9), 3382–3385 (1999). doi:10.1210/jcem.84.9.6105

    Article  CAS  PubMed  Google Scholar 

  26. T. Yanase, H. Sasano, T. Yubisui, Y. Sakai, R. Takayanagi, H. Nawata, Immunohistochemical study of cytochrome b5 in human adrenal gland and in adrenocortical adenomas from patients with Cushing’s syndrome. Endocrine J. 45(1), 89–95 (1998)

    Article  CAS  Google Scholar 

  27. N. Huang, A. Dardis, W.L. Miller, Regulation of cytochrome b5 gene transcription by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells. Mol. Endocrinol. 19(8), 2020–2034 (2005). doi:10.1210/me.2004-0411

    Article  CAS  PubMed  Google Scholar 

  28. W. Arlt, F. Callies, J.C. van Vlijmen, I. Koehler, M. Reincke, M. Bidlingmaier, D. Huebler, M. Oettel, M. Ernst, H.M. Schulte, B. Allolio, Dehydroepiandrosterone replacement in women with adrenal insufficiency. N. Engl. J. Med. 341(14), 1013–1020 (1999). doi:10.1056/nejm199909303411401

    Article  CAS  PubMed  Google Scholar 

  29. W. Arlt, F. Callies, I. Koehler, J.C. van Vlijmen, M. Fassnacht, C.J. Strasburger, M.J. Seibel, D. Huebler, M. Ernst, M. Oettel, M. Reincke, H.M. Schulte, B. Allolio, Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. J. Clin. Endocrinol. Metab. 86(10), 4686–4692 (2001). doi:10.1210/jcem.86.10.7974

    Article  CAS  PubMed  Google Scholar 

  30. F. Hammer, D.G. Drescher, S.B. Schneider, M. Quinkler, P.M. Stewart, B. Allolio, W. Arlt, Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging. J. Clin. Endocrinol. Metab. 90(11), 6283–6289 (2005). doi:10.1210/jc.2005-0915

    Article  CAS  PubMed  Google Scholar 

  31. A. Belanger, B. Candas, A. Dupont, L. Cusan, P. Diamond, J.L. Gomez, F. Labrie, Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J. Clin. Endocrinol. Metab. 79(4), 1086–1090 (1994). doi:10.1210/jcem.79.4.7962278

    Article  CAS  PubMed  Google Scholar 

  32. R.H. Straub, L. Konecna, S. Hrach, G. Rothe, M. Kreutz, J. Scholmerich, W. Falk, B. Lang, Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J. Clin. Endocrinol. Metab. 83(6), 2012–2017 (1998). doi:10.1210/jcem.83.6.4876

    Article  CAS  PubMed  Google Scholar 

  33. X. Belda, S. Fuentes, N. Daviu, R. Nadal, A. Armario, Stress-induced sensitization: the hypothalamic-pituitary-adrenal axis and beyond. Stress 18(3), 269–279 (2015). doi:10.3109/10253890.2015.1067678

    Article  CAS  PubMed  Google Scholar 

  34. A. Armario, C. Garcia-Marquez, M. Giralt, Previous chronic chlorimipramine treatment did not modify some physiological responses to acute and chronic stress in rats. Psychopharmacology 94(2), 217–220 (1988)

    Article  CAS  PubMed  Google Scholar 

  35. N. Daviu, C. Rabasa, R. Nadal, A. Armario, Comparison of the effects of single and daily repeated immobilization stress on resting activity and heterotypic sensitization of the hypothalamic-pituitary-adrenal axis. Stress 17(2), 176–185 (2014). doi:10.3109/10253890.2014.880834

    Article  CAS  PubMed  Google Scholar 

  36. T.E. Orr, J.L. Meyerhoff, E.H. Mougey, B.N. Bunnell, Hyperresponsiveness of the rat neuroendocrine system due to repeated exposure to stress. Psychoneuroendocrinology 15(5–6), 317–328 (1990)

    Article  CAS  PubMed  Google Scholar 

  37. B.H. Natelson, J.E. Ottenweller, J.A. Cook, D. Pitman, R. McCarty, W.N. Tapp, Effect of stressor intensity on habituation of the adrenocortical stress response. Physiol. Behav. 43(1), 41–46 (1988)

    Article  CAS  PubMed  Google Scholar 

  38. D.J. Morris, Why do humans have two glucocorticoids: a question of intestinal fortitude. Steroids 102, 32–38 (2015). doi:10.1016/j.steroids.2015.06.017

    Article  CAS  PubMed  Google Scholar 

  39. S.A. Andric, M.M. Janjic, N.J. Stojkov, T.S. Kostic, Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. Am. J. Physiol. Endocrinol. Metab. 299(4), E544–550 (2010). doi:10.1152/ajpendo.00337.2010

    Article  CAS  PubMed  Google Scholar 

  40. K.L. Saraiva, A.K. Silva, M.I. Wanderley, A.A. De Araujo, J.R. De Souza, C.A. Peixoto, Chronic treatment with sildenafil stimulates leydig cell and testosterone secretion. Int. J. Exp. Pathol. 90(4), 454–462 (2009). doi:10.1111/j.1365-2613.2009.00660.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. S.A. Andric, M.M. Janjic, N.J. Stojkov, T.S. Kostic, Protein kinase G-mediated stimulation of basal leydig cell steroidogenesis. Am. J. Physiol. Endocrinol. Metab. 293(5), E1399–1408 (2007). doi:10.1152/ajpendo.00482.2007

    Article  CAS  PubMed  Google Scholar 

  42. D. Demirbas, A.R. Wyman, M. Shimizu-Albergine, O. Cakici, J.A. Beavo, C.S. Hoffman, A yeast-based chemical screen identifies a PDE inhibitor that elevates steroidogenesis in mouse Leydig cells via PDE8 and PDE4 inhibition. PloS One 8(8), e71279 (2013). doi:10.1371/journal.pone.0071279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. M. Spitzer, S. Bhasin, T.G. Travison, M.N. Davda, H. Stroh, S. Basaria, Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology 1(6), 913–918 (2013). doi:10.1111/j.2047-2927.2013.00131.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. K. Jarvi, E. Dula, M. Drehobl, J. Pryor, J. Shapiro, M. Seger, Daily vardenafil for 6 months has no detrimental effects on semen characteristics or reproductive hormones in men with normal baseline levels. J. Urol. 179(3), 1060–1065 (2008). doi:10.1016/j.juro.2007.10.077

    Article  PubMed  Google Scholar 

  45. M.M. Kushnir, T. Blamires, A.L. Rockwood, W.L. Roberts, B. Yue, E. Erdogan, A.M. Bunker, A.W. Meikle, Liquid chromatography-tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals. Clin. Chem. 56(7), 1138–1147 (2010). doi:10.1373/clinchem.2010.143222

    Article  CAS  PubMed  Google Scholar 

  46. K. Nishimoto, K. Nakagawa, D. Li, T. Kosaka, M. Oya, S. Mikami, H. Shibata, H. Itoh, F. Mitani, T. Yamazaki, T. Ogishima, M. Suematsu, K. Mukai, Adrenocortical zonation in humans under normal and pathological conditions. J. Clini. Endocrinol. Metab. 95(5), 2296–2305 (2010). doi:10.1210/jc.2009-2010

    Article  CAS  Google Scholar 

  47. E.F. Nogueira, W.E. Rainey, Regulation of aldosterone synthase by activator transcription factor/cAMP response element-binding protein family members. Endocrinology 151(3), 1060–1070 (2010). doi:10.1210/en.2009-0977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. J. Nakashima, J. Brookins, B. Beckman, J.W. Fisher, Increased erythropoietin secretion in human hepatoma cells by N6-cyclohexyladenosine. Am. J. Physiol. 261(3 Pt 1), C455–460 (1991)

    Article  CAS  PubMed  Google Scholar 

  49. J.B. Sherwood, E.R. Burns, D. Shouval, Stimulation by cAMP of erythropoietin secretion by an established human renal carcinoma cell line. Blood 69(4), 1053–1057 (1987)

    CAS  PubMed  Google Scholar 

  50. J. Fandrey, A. Huwiler, S. Frede, J. Pfeilschifter, W. Jelkmann, Distinct signaling pathways mediate phorbol-ester-induced and cytokine-induced inhibition of erythropoietin gene expression. Eur. J. Biochem. 226(2), 335–340 (1994)

    Article  CAS  PubMed  Google Scholar 

  51. C. Batmunkh, J. Krajewski, W. Jelkmann, T. Hellwig-Burgel, Erythropoietin production: molecular mechanisms of the antagonistic actions of cyclic adenosine monophosphate and interleukin-1. FEBS Lett. 580(13), 3153–3160 (2006). doi:10.1016/j.febslet.2006.04.069

    Article  CAS  PubMed  Google Scholar 

  52. S. Bovio, A. Cataldi, G. Reimondo, P. Sperone, S. Novello, A. Berruti, P. Borasio, C. Fava, L. Dogliotti, G.V. Scagliotti, A. Angeli, M. Terzolo, Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J. Endocrinol. Invest. 29(4), 298–302 (2006). doi:10.1007/bf03344099

    Article  CAS  PubMed  Google Scholar 

  53. J.A. Ray, M.M. Kushnir, A.L. Rockwood, A.W. Meikle, Direct measurement of free estradiol in human serum and plasma by equilibrium dialysis-liquid chromatography-tandem mass spectrometry. Methods Mol. Biol. 1378, 99–108 (2016). doi:10.1007/978-1-4939-3182-8_12

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the “Associazione Scientifica in Endocrinologia, Andrologia e Metabolismo”, Carpi, Italy, for supporting the study. Bayer HealthCare, Italy, prepared and provided drug and placebo kits. Thanks to Dr. Diego Scannerini, Shimadsu, Italy, for the management of steroid measurements.

D.S. is recipient of a PhD fellowship of the doctorate in Clinical and Experimental Medicine of the University of Modena & Reggio Emilia.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Authors and Affiliations

  1. Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Daniele Santi, Elisa Pignatti, Vincenzo Rochira, Cesare Carani & Manuela Simoni

  2. Department of Medicine, Endocrinology, Metabolism and Geriatrics, Azienda USL of Modena, Modena, Italy

    Daniele Santi, Antonio RM Granata, Vincenzo Rochira & Manuela Simoni

  3. Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy

    Elisa Pignatti & Manuela Simoni

  4. Department of Laboratory Medicine and Pathological Anatomy, Azienda USL of Modena, Modena, Italy

    Tommaso Trenti & Laura Roli

  5. PerkinElmer, 20126, Milan, Italy

    Roberto Bozic

  6. SHIMADZU Italia, Milan, Italy

    Stefano Zaza

  7. Diabetic Service, Azienda USL of Modena, Modena, Italy

    Chiara Pacchioni

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  1. Daniele Santi
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Santi, D., Granata, A.R., Pignatti, E. et al. Effects of chronic administration of the phosphodiesterase inhibitor vardenafil on serum levels of adrenal and testicular steroids in men with type 2 diabetes mellitus. Endocrine 56, 426–437 (2017). https://doi.org/10.1007/s12020-016-1055-x

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